(a) Field of the Invention
The invention relates to novel 3-piperidinealkanamines and alkanamides, to compositions containing the same, and to the method of use thereof in the treatment of central nervous system disorders.
A number of know antipsychotic drugs are disclosed in the art which have been shown to share a selective, high affinity for sigma receptors, which are sites where psychotomimetic opiates, such as (+)-pentazocine and N-allylnormetazocine, act. It has been suggested that the antipsychotic behavioral profile of these antipsychotic drugs can be attributed to their role as competitive antagonists of sigma receptor binding and that a systematic screen for drugs that block sigma receptors may provide a valuable strategy for identifying novel antipsychotic agents. Additionally, it has been shown that the relative potencies of these agents studied in vivo correspond well with their relative binding affinities obtained in vitro. See, for example, Synder and Largent, J. Neuropsychiatry 1989, 1 (1), 7-15; Largent, et al., Eur. J. Pharmacol. 1988, 155, 345-347; Deutsch, et al., Clinical Neuropharmacology 1988, 11(2), 105-119; Tayler, et al., Drug Development Research 1987, 11, 65-70; Ferris, et al., Life Sciences 38(25), 2329-2337; and Su, et al., Neuroscience Letters 1986, 71, 224-228.
(b) Information Disclosure Statement
Welcher, U.S. Pat. No. 3,431,267, issued Mar. 4, 1969, discloses 2,3-dimethyl-3-piperidinepropanamine ##STR2## as a fungicide and pesticide.
Loew, et al., Endog. Exog. Opiate Agonists and Antagonists, E. L. Way, editor, Pergamon: Elmsford, New York 1980, pp 39-42, disclose 1-R.sub.1 -2,3,4,4-tetramethylpiperadines of general formula ##STR3## wherein R.sub.1 is 3-furanylmethyl, 2-furanylmethyl, 2-propenyl, cyclopropylmethyl, phenylethyl, methyl and hydrogen without an indication of utility.
Langer, et al., U.S. Pat. No. 5,023,266, issued Jun. 11, 1991, disclose compounds of the formula: ##STR4## wherein: R.sup.1 denotes a halogen atom or a hydroxy group;
R.sup.2 denotes a hydrogen atom or a methyl group; and PA1 R.sup.3 denotes a hydrogen or halogen atom. PA1 R.sup.2, R.sup.3 and R.sup.4 are the same or different lower-alkyl; PA1 n is zero or one; PA1 R.sup.5 is hydrogen, lower-alkyl, cycloalkyl, lower-alkoxy, phenyl, phenyl-lower-alkyl, phenyl-lower-alkyl in which the phenyl ring is substituted in the 2, 3, or 4-position by one to two, the same or different, halogen substituents, or R5 is a 5-membered aromatic monocyclic heterocycle containing from one to two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; and PA1 R.sup.6 is hydrogen or lower-alkyl; or when n is zero, R.sup.5 and R.sup.6 together are --(CH.sub.2).sub.m -- wherein m is an integer from four to six; PA1 R.sup.1 is lower-alkyl; PA1 R.sup.2, R.sup.3 and R.sup.4 are the same lower-alkyl; PA1 n is one; PA1 R.sup.5 is lower-alkoxy, phenyl-lower-alkyl in which the phenyl ring is substituted in the 2, 3, or 4-position by one or two chlorine substituents, or R.sup.5 is a 5-membered aromatic monocyclic heterocycle containing one heteroatom selected from the group consisting of oxygen and sulfur; and PA1 R.sup.6 is hydrogen or lower-alkyl. PA1 R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are methyl; PA1 n is one; PA1 R.sup.5 is lower-alkoxy, 3,4-dichlorophenyl-lower-alkyl, or thienyl; and PA1 R.sup.6 is hydrogen or methyl.
The compounds are said to be useful in the treatment of phychotic disorders.
Gray and Cheng, European Patent Application 445195, published Nov. 6, 1991, disclose a series of ethanobicyclic amine derivatives which are said to be useful in the treatment of CNS disorders such as psychotic disorders, convulsions, dystonia and cerebral ischemia.
Cain, et al., European Patent Application 449187, published Oct. 2, 1991, disclose a series of disubstituted piperidine ether derivatives which are said to be useful in treating physiological or drug induced psychosis or dyskinesia in mammals or fungal disease in plants.
Glennon, et al., J. Med. Chem. 1991. 34, 3360-3365, disclose a series of novel 4-phenylpiperidine derivatives which are stated to bind with high affinity to sigma receptors.